Field of the Invention
The present invention relates to methods for inhibiting expression of ASC (apoptosis-related speck-like protein containing a caspase recruitment domain [CARD]), expression of NLRP3 (NLR family, pyrin domain containing 3), and/or formation of NLRP3 inflammasome complex. In particular, the invention relates to methods for the treatment and/or prevention of a disorder mediated by ASC and/or NLRP3, and/or by formation of NLRP3 inflammasome complex by using diacerein or its analogs. Pharmaceutical compositions comprising diacerein or its analogs are also provided.
Description of the Related Art
Nucleotide-binding oligomerization domain-like receptors (NLRs) are an evolutionarily conserved family of cytosolic receptors with a tripartite structure that share a common central nucleotide-binding and oligomerization (NACHT) domain that is usually flanked by a C-terminal leucine-rich repeat (LRR) domain and a N-terminal effector pyrin domain (PYD) or a caspase recruitment domain (CARD). Once activated by pathogen-associated molecules or damage-associated molecules, NLRs oligomerize and recruit the adaptor protein ASC and the cysteine protease procaspase-1 and form an inflammasome complex, leading to the autocatalysis and activation of caspase-1. Active caspase-1 ultimately cleaves the precursor proinflammatory cytokines pro-IL-1β and pro-IL-18 into their mature secreted forms.
The formation of inflammasome complex from NLRs has been implicated in the pathogenesis of a wide variety of diseases, including inherited autoinflammatory conditions as well as chronic diseases. In particular, it has been linked to diseases such as Alzheimer's disease atherosclerosis, metabolic syndrome, and age-related macular degeneration.
Based on the above mentioned mechanism, suppressing NLRs or ASC and the formation of inflammasome complex has been considered as a potential way to treat the diseases mediated by these proteins (Ozaki et al., Journal of Inflammation Research 2015, 8:15-27).
US Publication No. 2014/0199320 discloses a method for the treatment of acne through inhibition of IL-1β, NLRP3, ASC, IL-1 receptor type 1, caspase-1 or cathepsin B by numerous inhibitors including IL-1β inhibitors. However, it focuses on suppression of IL-1β, rather than NLRP3 and ASC, and thus gives little clue on which inhibitors would have direct inhibitory effect on NLRP3 and ASC.
Besides, many reagents that target IL-1β and IL-18 (the products from inflammasome activation) have been developed to treat inflammatory diseases, including anakinra (a recombinant IL-1 receptor antagonist), canakinurnab (an IL-1β antibody), rilonacept (a soluble decoy IL-1 receptor), IL-18 binding, protein, soluble IL-18 receptors and anti-IL-18 receptor monoclonal antibodies, but these reagents suppress IL-1β or IL-18, not NLRP3 and ASC.
Therefore, there is still a need in the art for specific methods and compounds which are able to suppress NLRs or ASC and to inhibit the formation of inflammasome complex.